Classic studies in embryology and contemporary research in immunology and molecular biology have disclosed the carefully orchestrated events leading to development of the immune system and immunoregulation that ultimately provide immunohomeostasis. During ontogeny, the pluripotential stem cell emerges and differentiates into all hematopoietic lineages, including three major immunologically relevant components: T-cell differentiation occurs within the thymus; B cells appear within fetal liver, adult bone marrow, and possibly other abdominal sites; and concurrently, the monocyte-macrophage system develops. Under the influence of an array of cytokines and cellular interactions, immune regulation is established. T and B lymphocytes elaborate genetically encoded messages that acquire specificity via transposable genetic elements. Receptors and cytokines provide immune recognition, communication, regulation, and memory for antigens. Inherited and acquired defects in ontogeny and immune regulation are the basis for immunodeficiency disorders.